TY - JOUR T1 - Activation of Corticotropin-Releasing Factor Receptor 1 Selectively Inhibits Ca<sub>V</sub>3.2 T-Type Calcium Channels JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1596 LP - 1609 DO - 10.1124/mol.107.043612 VL - 73 IS - 6 AU - Jin Tao AU - Michael E. Hildebrand AU - Ping Liao AU - Mui Cheng Liang AU - Gregory Tan AU - Shengnan Li AU - Terrance P. Snutch AU - Tuck Wah Soong Y1 - 2008/06/01 UR - http://molpharm.aspetjournals.org/content/73/6/1596.abstract N2 - The corticotropin-releasing factor (CRF) peptides CRF and uro-cortins 1 to 3 are crucial regulators of mammalian stress and inflammatory responses, and they are also implicated in disorders such as anxiety, depression, and drug addiction. There is considerable interest in the physiological mechanisms by which CRF receptors mediate their widespread effects, and here we report that the native CRF receptor 1 (CRFR1) endogenous to the human embryonic kidney 293 cells can functionally couple to mammalian CaV3.2 T-type calcium channels. Activation of CRFR1 by either CRF or urocortin (UCN) 1 reversibly inhibits CaV3.2 currents (IC50 of ∼30 nM), but it does not affect CaV3.1 or CaV3.3 channels. Blockade of CRFR1 by the antagonist astressin abolished the inhibition of CaV3.2 channels. The CRFR1-dependent inhibition of CaV3.2 channels was independent of the activities of phospholipase C, tyrosine kinases, Ca2+/calmodulin-dependent protein kinase II, protein kinase C, and other kinase pathways, but it was dependent upon a cholera toxin-sensitive G protein-mediated mechanism relying upon G protein βγ subunits (Gβγ). The inhibition of CaV3.2 channels via the activation of CRFR1 was due to a hyperpolarized shift in their steady-state inactivation, and it was reversible upon washout of the agonists. Given that UCN affect multiple aspects of cardiac and neuronal physiology and that CaV3.2 channels are widespread throughout the cardiovascular and nervous systems, the results point to a novel and functionally relevant CRFR1-CaV3.2 T-type calcium channel signaling pathway. The American Society for Pharmacology and Experimental Therapeutics ER -